title: Serotonin 2A receptors contribute to the regulation of risk-averse decisions.
abstract: Pharmacological studies point to a role of the neurotransmitter serotonin (5-HT) in regulating the preference for risky decisions, yet the functional contribution of specific 5-HT receptors remains to be clarified. We used pharmacological fMRI to investigate the role of the 5-HT2A receptors in processing negative outcomes and regulating risk-averse behavior. During fMRI, twenty healthy volunteers performed a gambling task under two conditions: with or without blocking the 5-HT2A receptors. The volunteers repeatedly chose between small, likely rewards and large, unlikely rewards. Choices were balanced in terms of expected utility and potential loss. Acute blockade of the 5-HT2A receptors with ketanserin made participants more risk-averse. Ketanserin selectively reduced the neural response of the frontopolar cortex to negative outcomes that were caused by low-risk choices and were associated with large missed rewards. In the context of normal 5-HT2A receptor function, ventral striatum displayed a stronger response to low-risk negative outcomes in risk-taking as opposed to risk-averse individuals. This (negative) correlation between the striatal response to low-risk negative outcomes and risk-averse choice behavior was abolished by 5-HT2A receptor blockade. The results provide the first evidence for a critical role of 5-HT2A receptor function in regulating risk-averse behavior. We suggest that the 5-HT2A receptor system facilitates risk-taking behavior by modulating the outcome evaluation of "missed" reward. These results have implications for understanding the neural basis of abnormal risk-taking behavior, for instance in pathological gamblers.
authors.affiliation: Danish Research Centre for Magnetic Resonance, Copenhagen University Hospital, Hvidovre, Denmark; Center for Integrated Molecular Brain Imaging, Copenhagen University Hospital, Copenhagen, Denmark. Electronic address: julianm@drcmr.dk.
authors.forename: Julian
authors.initials: J
authors.lastname: Macoveanu
authors.forename: James B
authors.initials: JB
authors.lastname: Rowe
authors.forename: Bettina
authors.initials: B
authors.lastname: Hornboll
authors.forename: Rebecca
authors.initials: R
authors.lastname: Elliott
authors.forename: Olaf B
authors.initials: OB
authors.lastname: Paulson
authors.forename: Gitte M
authors.initials: GM
authors.lastname: Knudsen
authors.forename: Hartwig R
authors.initials: HR
authors.lastname: Siebner
mesh_terms: D000328:Adult; D001362:Avoidance Learning / Q000502:physiology*; D001931:Brain Mapping; D003657:Decision Making / Q000502:physiology*; D005260:Female; D005625:Frontal Lobe / Q000502:physiology*; D005715:Gambling; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D012201:Reward; D040242:Risk Reduction Behavior; D059326:Serotonergic Neurons / Q000502:physiology*
chemical_list: D044402:Receptor, Serotonin, 5-HT2A
keywords: Decision-making; Frontopolar cortex; Ketanserin; Pharmacological fMRI; Reward; Serotonin